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Small Guanosine Triphospatase RhoA and Rho-Associated Kinase as Regulators of Trophoblast Migration

Departments of Obstetrics and Gynecology (S.S., M.I., K.S., H.H., M.K.S., Y.N.), Anatomy (Y.A.), and Biochemistry (S.N.), Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan; Department of Obstetrics and Gynecology (Y.Y.), Keio University School of Medicine, Shinanomachi, Tokyo, 160-8582, Japan; and Mitsubishi Pharma Corporation (M.U.), Aoba-Ku, Yokohama 227-0033, Japan

Address all correspondence and requests for reprints to: Shigetatsu Shiokawa, M.D., Ph.D., Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka City, Tokyo 181-8611, Japan. E-mail: shiochan{at}kyorin-u.ac.jp.

Abstract

The small guanosine triphosphatase Rho controls cell adhesion and motility through reorganization of the actin cyto-skeleton and regulation of actomyosin contractility. Among the putative target molecules of Rho, a Rho-associated coiled coil-forming protein kinase (ROCK) is thought to participate in Rho-mediated cell adhesion and motility. In the present study, we explored the expression and function of RhoA and ROCK in human trophoblast cells. The colocalization of RhoA, cytokeratin 8/18, and cytokeratin 7 in some cells located in the decidual stromal region indicated that extravillous trophoblast cells expressed RhoA. In double staining for RhoA and ROCK in human chorionic villi, RhoA staining was strongly positive in the cytoplasm of cytotrophoblasts, whereas ROCK stained in the cytoplasm of cytotrophoblasts and syncytiotrophoblasts. Both RhoA and ROCK were stained in cytoplasma of cultured human cytotrophoblast. Cultured human trophoblast cells contained actin stress fibers that were lost after treatment with C3, an exoenzyme produced by Clostridium botulinum. Y-27632, a selective ROCK inhibitor, suppressed RhoA-induced formation of actin stress fibers and formation of focal contact in trophoblast cells. The trophoblast reacquired actin stress fibers and focal contact after withdrawal of Y-27632. Cultured human cytotrophoblast cells from 7–9 wk of gestation migrated into a fibronectin-coated membrane. Both C3 exoenzyme and Y-27632 inhibited cytotrophoblast migration in a dose-dependent manner. In conclusion, cyto-trophoblasts express RhoA and ROCK in their cytoplasm, and RhoA-ROCK is involved in their assembly of actin stress fibers. Suppression of RhoA-ROCK reduces trophoblast migration. These findings suggest that RhoA-ROCK signaling is a key regulator of trophoblast cell migration.

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